Insulin dependent diabetes mellitus (IDDM), a disease state occurring in 0.3% of the general population, is associated with insufficient insulin production causing metabolic changes such as hyperglycemia, glycosuria and decreased hepatic glycogen levels. Clinically, the disease is first observed as causing ravenous hunger, frequent urination and unquenchable thirst. Even with exogenously supplied insulin treatment, complications such as retinopathy, neuropathy, peripheral vascular disease, atherosclerosis, weight loss, stroke, renal failure, and coma leading to death occur.
The etiology of IDDM is attributed to an autoimmune response to the .beta.-islet cells. The pancreatic islets become infiltrated with lymphocytes (insulitis) and the insulin-producing .beta.-cells are destroyed. Approximately 80% of the .beta.-cells are destroyed before clinically observable symptoms occur. Adoptive transfer studies in NOD mice [DV Serreze, Diabetes 37: 252 (1988)] have shown that T-cell mediated events occur initially in IDDM while humoral abnormalities (cytoplasmic islet cell, insulin, and 64 Kd protein autoantibodies) contribute later during the disease progression [M. A. Atkinson, Scientific Am. 62 (1990)]. Genetic susceptibility involving class II major histocompatability complex (MHC) appears to play a major role in this autoimmune disease. Approximately 60-70% of this susceptibility resides in the HLA region. [A. C. Tarn, Lancet 845 (1988)]. More than 95% of those individuals with IDDM are HLA DR3 and/or DR4 positive, whereas DR2 is negatively associated with the disease. [K. Wilson, Ann. Rev. Med. 41: 497 (1990)].
As treatment of IDDM with supplemental insulin is not completely satisfactory, current research has focused on developing agents for the treatment and prevention of IDDM. Several animal models have been utilized to study the etiology of IDDM and to evaluate potential forms of treatment and prevention.
Two standard animal models have been developed that emulate human IDDM. The first standard animal model, developed by Tochino [Exerpta Medica, 295 (1982)], the non-obese diabetic (NOD) mouse, is a mouse strain that spontaneously develops IDDM. Insulitis is initially observed at about 30 days of age, and by 140 days of age, approximately 70% of the female NOD mice develop IDDM. Marked mononuclear cell infiltration surrounding and/or invading Langerhans' islets with concomitant .beta.-cell destruction are also observed. [Y. Mori, Diabetalogia 29: 244 (1986)]. The second standard animal model is the Bio Breeding (BB) rat, which develops gross abnormalities of the immune response including a T-cell lymphopenia preceding and accompanying the onset of IDDM. [C. R. Stiller, Science 223: 1362 (1984)].
The immunosuppressants cyclosporin A (CsA) and FK-506 have been evaluated in the BB rat and NOD mouse models of IDDM, and CsA has been evaluated in human clinical trials. CsA has been shown to be effective in prophylactically preventing the onset of IDDM and insulitis in both the NOD mouse and BB rat standard animal models, but was only partially effective in ameliorating IDDM when first administered after the onset of the initial symptoms of IDDM. [B. Formby, J. Pharm. Exp. Ther. 241: 106 (1987); C. R. Stiller, Metabolism 32 Supp 1: 69 (1983); and M. A. Jaworski, Clin. Invest. Med. 10: 488 (1987)]. One study reported that CsA had little therapeutic effect on IDDM in the NOD mouse standard animal model after the onset of IDDM. [Y. Mori, Diabetologia 29: 244 (1986)].
CsA has been evaluated in several clinical studies in newly diagnosed IDDM patients. CsA treatment was shown to reduce the dosage requirement of exogenously administered insulin and induced remission (non-insulin dependence) in about 23 to 50% of patients in these studies for up to 1 year. The percent of remission was highest in patients who started CsA treatment the earliest after IDDM diagnosis. Data on the longevity of remission following cessation of CsA treatment is inconclusive. One study reported remissions lasting for more than 9 months, whereas several other studies reported that remission was not maintained following discontinuation of CsA treatment. [G. Feutren, Lancet 119: (1986); J. Dupre, Diabetes 37: 1574, (1988); C. R. Stiller, Science 223: 1362 (1984); R. Lipton, Diabetes Care, 13: 776 (1990); K. Wilson, Annu. Rev. Med. 41: 497 (1990)].
FK-506 has been demonstrated to prevent the onset of IDDM in both the NOD and BB standard animal models of IDDM. Two studies have shown that FK-506 induced prevention of IDDM lasted 45 days and 20 weeks, respectively, beyond termination of FK-506 treatment in about 75% of animals that had not developed IDDM when FK-506 treatment was discontinued. [N. Murase, Diabetes 39: 1584 (1990); K. Kurasawa, Clin. Immun. Immunopath. 57: 274 (1990); J. Miyagawa, Diabetologia 33: 503 (1990)].
Rapamycin, a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus [U.S. Pat. No. 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Martel, R., Can. J. Physiol. Pharm. 55: 48 (1977)], inhibit murine T-cell activation [Staruch, M., FASEB 3: 3411 (1989)], and prolong survival time of organ grafts in histoincompatible rodents [Morris, R., Med. Sci. Res. 17: 877 (1989)].